PROJECT DESCRIPTION Epigenetic mechanisms have gained increasing recognition for their role in cancer development and progression. In particular, characterization of epigenetic dysregulation in leukemia has led to the development of potential targeted therapy. Comparison of epigenetic marks in leukemia stem cells and their normal counterparts revealed a loss of histone H3 lysine9 dimethylation (H3K9me2) at promoters of oncogenes essential for MLL-AF9 leukemia. Preliminary data suggest that Jmjd1c, a histone H3K9me2/1 demethylase and direct target of MLL-AF9, is responsible for removing repressive H3K9me2 mark and de-repressing oncogenes in MLL-AF9 leukemia. The overall goal of this proposal is to assess the role of Jmjd1c in normal hematopoiesis as well as in MLL-AF9 leukemogenesis. Specifically Jmjd1c will be conditionally deleted in hematopoiesis in adult mice to characterize its role in hematopoiesis and leukemia. The role of JMJD1C in human leukemia will be tested by shRNA mediated suppression of JMJD1C in mice bearing human leukemic cells. Additionally, detailed analysis of chromatin and gene expression changes associated with loss of Jmjd1c will be performed to gain important mechanistic insights. The specific aims are: 1: To establish Jmjd1c as therapeutic target in MLL-AF9 leukemia. 2: To evaluate the role of Jmjd1c in normal hematopoiesis. Dr. Nan Zhu is currently a research fellow in the Department of Hematology/Oncology at Children's Hospital Boston and will be an instructor in the Human Oncology & Pathogenesis Program at Memorial Sloan Kettering Cancer Center. Building on her scientific training in epigenetic regulation and experimental hematology, Dr. Zhu uncovered and is now investigating the role of Jmjd1c in MLL-AF9 leukemia to assess its therapeutic potential. Dr. Zhu will carry out her proposed project in a rich academic institutional environment under the mentorship of Dr. Scott Armstrong, recognized leader in leukemia field. Dr. Armstrong has proposed a career- development plan to further Dr. Zhu's scientific development and to help her transition to independence.